BRENDA - Enzyme Database
show all sequences of 1.5.1.5

Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases

Christensen, K.E.; Mackenzie, R.E.; Vitam. Horm. 79, 393-410 (2008)

Data extracted from this reference:

Cloned(Commentary)
Cloned (Commentary)
Organism
deletion of the MIS1 gene has little effect
Saccharomyces cerevisiae
null mutation is embryonic lethal at about 12 days gestation, knockout of enzyme establishes the important role of formate production during embryogenesis
Homo sapiens
Engineering
Protein Variants
Commentary
Organism
D133E
mutant retains no dehydrogenase activity
Homo sapiens
D133E
no dehydrogenase activity retained, Mg2+ binding site
Homo sapiens
K56Q/Q100K
retaines two-third of dehydrogenase activity but no cyclohydrolase activity
Homo sapiens
K56Q/Q100K
site-directed mutagenesis shows that the double mutant has no cyclohydrolase activity but retains two-thirds of the normal dehydrogenase activity
Homo sapiens
additional information
asparagine-125 is required for folate-substrate binding, arginine-173 mutation causes 500fold increase in the Km for NADP, serine-197 mutation a 20fold increase
Homo sapiens
additional information
knockout mutant of MTHFD2 is embryonic lethal in mice at about 12 days gestation, no normal development of hematogenesis in the liver
Homo sapiens
additional information
mutation of arginine-166 leads to complete loss of dehydrogenase activity, is critically responsible for binding of the inorganic phosphate, with arginine-198 mutation some dehydrogenase activity is retained, it probably only assists in phosphate binding
Homo sapiens
Inhibitors
Inhibitors
Commentary
Organism
Structure
phosphate
competitive inhibitor against NADP+
Homo sapiens
KM Value [mM]
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
additional information
-
NADP+
mutation of Arg173 causes a 500fold increase in the Km value for NADP+, while mutation of Ser197 causes a 20fold increase
Homo sapiens
Localization
Localization
Commentary
Organism
GeneOntology No.
Textmining
cytoplasm
-
Homo sapiens
5737
-
cytosol
ADE3
Saccharomyces cerevisiae
5829
-
mitochondrion
-
Homo sapiens
5739
-
mitochondrion
MIS1
Saccharomyces cerevisiae
5739
-
Metals/Ions
Metals/Ions
Commentary
Organism
Structure
inorganic phosphate
required for activity, competitive inhibitor of NADP
Homo sapiens
Mg2+
required for activity
Homo sapiens
Mg2+
absolutely required for activity
Homo sapiens
Mn2+
required for activity when Mg2+ is absent
Homo sapiens
Molecular Weight [Da]
Molecular Weight [Da]
Molecular Weight Maximum [Da]
Commentary
Organism
34000
-
MTHFD2 evolves from a trifunctional dehydrogenase-cyclohydrolase-synthetase precursor with the loss of synthetase function
Homo sapiens
Natural Substrates/ Products (Substrates)
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
ID
5,10-methylene tetrahydrofolate + NAD+
Homo sapiens
bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities
5,10-methenyl tetrahydrofolate + NADH + H+
-
-
r
5,10-methylene tetrahydrofolate + NADP+
Saccharomyces cerevisiae
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities
5,10-methenyl tetrahydrofolate + NADPH
-
-
r
5,10-methylene tetrahydrofolate + NADP+
Homo sapiens
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities
5,10-methenyl tetrahydrofolate + NADPH + H+
-
-
r
5,10-methylene-tetrahydrofolate + NAD+
Homo sapiens
combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase
5,10-methenyl-tetrahydrofolate + NADH
50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
-
r
5,10-methylene-tetrahydrofolate + NADP+
Homo sapiens
-
5,10-methenyl-tetrahydrofolate + NADPH + H+
the cyclohydrolase forms formyltetrahydrofolate
-
r
5,10-methylenetetrahydrofolate + NADP+
Homo sapiens
-
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
r
additional information
Saccharomyces cerevisiae
the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions
?
-
-
?
Organism
Organism
UniProt
Commentary
Textmining
Homo sapiens
-
-
-
Homo sapiens
-
enzyme is unique in mammals
-
Saccharomyces cerevisiae
-
-
-
Source Tissue
Source Tissue
Commentary
Organism
Textmining
ascites tumor cell
-
Homo sapiens
-
additional information
the cytoplasmatic MTHFD1 is ubiquitously expressed in all mammalian cells
Homo sapiens
-
additional information
the mitochondrial MTHFD2 is detected only in transformed cell lines and embryogenic tissues
Homo sapiens
-
Substrates and Products (Substrate)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
Substrate Product ID
5,10-methylene tetrahydrofolate + NAD+
bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities
701402
Homo sapiens
5,10-methenyl tetrahydrofolate + NADH + H+
-
-
-
r
5,10-methylene tetrahydrofolate + NADP+
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities
701402
Saccharomyces cerevisiae
5,10-methenyl tetrahydrofolate + NADPH
-
-
-
r
5,10-methylene tetrahydrofolate + NADP+
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities
701402
Homo sapiens
5,10-methenyl tetrahydrofolate + NADPH + H+
-
-
-
r
5,10-methylene-tetrahydrofolate + NAD+
combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase
701402
Homo sapiens
5,10-methenyl-tetrahydrofolate + NADH
50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
-
-
r
5,10-methylene-tetrahydrofolate + NADP+
-
701402
Homo sapiens
5,10-methenyl-tetrahydrofolate + NADPH + H+
the cyclohydrolase forms formyltetrahydrofolate
-
-
r
5,10-methylenetetrahydrofolate + NADP+
-
701402
Homo sapiens
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
r
additional information
the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions
701402
Saccharomyces cerevisiae
?
-
-
-
?
Synonyms
Synonyms
Commentary
Organism
ADE3
-
Saccharomyces cerevisiae
dehydrogenasse-cyclohydrolase-synthetase
-
Saccharomyces cerevisiae
methylenetetrahydrofolate dehydrogenase
-
Homo sapiens
methylenetetrahydrofolate dehydrogenase
-
Saccharomyces cerevisiae
MIS1
-
Saccharomyces cerevisiae
mitochondrial methylenetetrahydrofolate dehydrogenase
-
Homo sapiens
MTHFD1
-
Homo sapiens
MTHFD1 protein
trifunctional cytosolic NADP(+)-dependent methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase
Homo sapiens
MTHFD2
-
Homo sapiens
MTHFD2 protein
bifunctional mitochondrial NAD(+)-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase, derived from trifunctional precursor by loss of the formyltetrahydrofolate synthetase domain, unique in mammals
Homo sapiens
NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase
-
Homo sapiens
Cofactor
Cofactor
Commentary
Organism
Structure
NAD+
instead of NADP as in cytosolic dehydrogenase precursor (higher Km and lower Vmax with NADP)
Homo sapiens
NAD+
mitochondrial dehydrogenase activity
Homo sapiens
NADP+
-
Homo sapiens
NADP+
-
Saccharomyces cerevisiae
NADP+
reverse cyclohydrolase activity is stimulated by the NADP analog 2',5'-ADP twofold
Homo sapiens
NADP+
the hydrogenase can also us NADP+ but with a higher Km value and lower Vmax than NAD+
Homo sapiens
Cloned(Commentary) (protein specific)
Commentary
Organism
deletion of the MIS1 gene has little effect
Saccharomyces cerevisiae
null mutation is embryonic lethal at about 12 days gestation, knockout of enzyme establishes the important role of formate production during embryogenesis
Homo sapiens
Cofactor (protein specific)
Cofactor
Commentary
Organism
Structure
NAD+
instead of NADP as in cytosolic dehydrogenase precursor (higher Km and lower Vmax with NADP)
Homo sapiens
NAD+
mitochondrial dehydrogenase activity
Homo sapiens
NADP+
-
Homo sapiens
NADP+
-
Saccharomyces cerevisiae
NADP+
reverse cyclohydrolase activity is stimulated by the NADP analog 2',5'-ADP twofold
Homo sapiens
NADP+
the hydrogenase can also us NADP+ but with a higher Km value and lower Vmax than NAD+
Homo sapiens
Engineering (protein specific)
Protein Variants
Commentary
Organism
D133E
mutant retains no dehydrogenase activity
Homo sapiens
D133E
no dehydrogenase activity retained, Mg2+ binding site
Homo sapiens
K56Q/Q100K
retaines two-third of dehydrogenase activity but no cyclohydrolase activity
Homo sapiens
K56Q/Q100K
site-directed mutagenesis shows that the double mutant has no cyclohydrolase activity but retains two-thirds of the normal dehydrogenase activity
Homo sapiens
additional information
asparagine-125 is required for folate-substrate binding, arginine-173 mutation causes 500fold increase in the Km for NADP, serine-197 mutation a 20fold increase
Homo sapiens
additional information
knockout mutant of MTHFD2 is embryonic lethal in mice at about 12 days gestation, no normal development of hematogenesis in the liver
Homo sapiens
additional information
mutation of arginine-166 leads to complete loss of dehydrogenase activity, is critically responsible for binding of the inorganic phosphate, with arginine-198 mutation some dehydrogenase activity is retained, it probably only assists in phosphate binding
Homo sapiens
Inhibitors (protein specific)
Inhibitors
Commentary
Organism
Structure
phosphate
competitive inhibitor against NADP+
Homo sapiens
KM Value [mM] (protein specific)
KM Value [mM]
KM Value Maximum [mM]
Substrate
Commentary
Organism
Structure
additional information
-
NADP+
mutation of Arg173 causes a 500fold increase in the Km value for NADP+, while mutation of Ser197 causes a 20fold increase
Homo sapiens
Localization (protein specific)
Localization
Commentary
Organism
GeneOntology No.
Textmining
cytoplasm
-
Homo sapiens
5737
-
cytosol
ADE3
Saccharomyces cerevisiae
5829
-
mitochondrion
-
Homo sapiens
5739
-
mitochondrion
MIS1
Saccharomyces cerevisiae
5739
-
Metals/Ions (protein specific)
Metals/Ions
Commentary
Organism
Structure
inorganic phosphate
required for activity, competitive inhibitor of NADP
Homo sapiens
Mg2+
required for activity
Homo sapiens
Mg2+
absolutely required for activity
Homo sapiens
Mn2+
required for activity when Mg2+ is absent
Homo sapiens
Molecular Weight [Da] (protein specific)
Molecular Weight [Da]
Molecular Weight Maximum [Da]
Commentary
Organism
34000
-
MTHFD2 evolves from a trifunctional dehydrogenase-cyclohydrolase-synthetase precursor with the loss of synthetase function
Homo sapiens
Natural Substrates/ Products (Substrates) (protein specific)
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
ID
5,10-methylene tetrahydrofolate + NAD+
Homo sapiens
bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities
5,10-methenyl tetrahydrofolate + NADH + H+
-
-
r
5,10-methylene tetrahydrofolate + NADP+
Saccharomyces cerevisiae
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities
5,10-methenyl tetrahydrofolate + NADPH
-
-
r
5,10-methylene tetrahydrofolate + NADP+
Homo sapiens
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities
5,10-methenyl tetrahydrofolate + NADPH + H+
-
-
r
5,10-methylene-tetrahydrofolate + NAD+
Homo sapiens
combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase
5,10-methenyl-tetrahydrofolate + NADH
50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
-
r
5,10-methylene-tetrahydrofolate + NADP+
Homo sapiens
-
5,10-methenyl-tetrahydrofolate + NADPH + H+
the cyclohydrolase forms formyltetrahydrofolate
-
r
5,10-methylenetetrahydrofolate + NADP+
Homo sapiens
-
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
r
additional information
Saccharomyces cerevisiae
the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions
?
-
-
?
Source Tissue (protein specific)
Source Tissue
Commentary
Organism
Textmining
ascites tumor cell
-
Homo sapiens
-
additional information
the cytoplasmatic MTHFD1 is ubiquitously expressed in all mammalian cells
Homo sapiens
-
additional information
the mitochondrial MTHFD2 is detected only in transformed cell lines and embryogenic tissues
Homo sapiens
-
Substrates and Products (Substrate) (protein specific)
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
ID
5,10-methylene tetrahydrofolate + NAD+
bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities
701402
Homo sapiens
5,10-methenyl tetrahydrofolate + NADH + H+
-
-
-
r
5,10-methylene tetrahydrofolate + NADP+
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities
701402
Saccharomyces cerevisiae
5,10-methenyl tetrahydrofolate + NADPH
-
-
-
r
5,10-methylene tetrahydrofolate + NADP+
trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities
701402
Homo sapiens
5,10-methenyl tetrahydrofolate + NADPH + H+
-
-
-
r
5,10-methylene-tetrahydrofolate + NAD+
combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase
701402
Homo sapiens
5,10-methenyl-tetrahydrofolate + NADH
50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate
-
-
r
5,10-methylene-tetrahydrofolate + NADP+
-
701402
Homo sapiens
5,10-methenyl-tetrahydrofolate + NADPH + H+
the cyclohydrolase forms formyltetrahydrofolate
-
-
r
5,10-methylenetetrahydrofolate + NADP+
-
701402
Homo sapiens
5,10-methenyltetrahydrofolate + NADPH + H+
-
-
-
r
additional information
the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions
701402
Saccharomyces cerevisiae
?
-
-
-
?
General Information
General Information
Commentary
Organism
metabolism
cytosolic protein with role in cytosolic purine synthesis, ubiquitously expressed in all mammalian cells
Homo sapiens
metabolism
mitochondrial protein with role in cytosolic purine synthesis (main switch for format production in mitochondria) during embryonic development and in cells undergoing rapid growth, not expressed in differentiated cells
Homo sapiens
General Information (protein specific)
General Information
Commentary
Organism
metabolism
cytosolic protein with role in cytosolic purine synthesis, ubiquitously expressed in all mammalian cells
Homo sapiens
metabolism
mitochondrial protein with role in cytosolic purine synthesis (main switch for format production in mitochondria) during embryonic development and in cells undergoing rapid growth, not expressed in differentiated cells
Homo sapiens
Other publictions for EC 1.5.1.5
No.
1st author
Pub Med
title
organims
journal
volume
pages
year
Activating Compound
Application
Cloned(Commentary)
Crystallization (Commentary)
Engineering
General Stability
Inhibitors
KM Value [mM]
Localization
Metals/Ions
Molecular Weight [Da]
Natural Substrates/ Products (Substrates)
Organic Solvent Stability
Organism
Oxidation Stability
Posttranslational Modification
Purification (Commentary)
Reaction
Renatured (Commentary)
Source Tissue
Specific Activity [micromol/min/mg]
Storage Stability
Substrates and Products (Substrate)
Subunits
Synonyms
Temperature Optimum [°C]
Temperature Range [°C]
Temperature Stability [°C]
Turnover Number [1/s]
pH Optimum
pH Range
pH Stability
Cofactor
Ki Value [mM]
pI Value
IC50 Value
Activating Compound (protein specific)
Application (protein specific)
Cloned(Commentary) (protein specific)
Cofactor (protein specific)
Crystallization (Commentary) (protein specific)
Engineering (protein specific)
General Stability (protein specific)
IC50 Value (protein specific)
Inhibitors (protein specific)
Ki Value [mM] (protein specific)
KM Value [mM] (protein specific)
Localization (protein specific)
Metals/Ions (protein specific)
Molecular Weight [Da] (protein specific)
Natural Substrates/ Products (Substrates) (protein specific)
Organic Solvent Stability (protein specific)
Oxidation Stability (protein specific)
Posttranslational Modification (protein specific)
Purification (Commentary) (protein specific)
Renatured (Commentary) (protein specific)
Source Tissue (protein specific)
Specific Activity [micromol/min/mg] (protein specific)
Storage Stability (protein specific)
Substrates and Products (Substrate) (protein specific)
Subunits (protein specific)
Temperature Optimum [°C] (protein specific)
Temperature Range [°C] (protein specific)
Temperature Stability [°C] (protein specific)
Turnover Number [1/s] (protein specific)
pH Optimum (protein specific)
pH Range (protein specific)
pH Stability (protein specific)
pI Value (protein specific)
Expression
General Information
General Information (protein specific)
Expression (protein specific)
KCat/KM [mM/s]
KCat/KM [mM/s] (protein specific)
755732
Bueno
An assessment of three human ...
Homo sapiens
Acta Crystallogr. Sect. F
75
148-152
2019
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1
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1
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1
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757625
Sah
Utilisation of 10-formyldihyd ...
Escherichia coli, Escherichia coli K12
Microbiology
164
982-991
2018
-
-
1
-
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-
-
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-
1
2
-
3
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1
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4
1
1
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1
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1
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1
2
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1
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4
1
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1
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1
1
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757773
Hitzel
Oxidized phospholipids regula ...
Homo sapiens
Nat. Commun.
9
2292
2018
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-
-
-
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1
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1
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1
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1
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1
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1
1
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756334
Shin
Human mitochondrial MTHFD2 is ...
Homo sapiens
Cancer Metab.
5
11
2017
-
-
2
-
-
-
-
4
2
-
2
2
-
2
-
-
2
-
-
3
-
-
10
-
5
-
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4
-
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4
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2
4
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4
2
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2
2
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2
-
3
-
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10
-
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4
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2
2
-
4
4
743250
Aluri
Physiological role of FolD (m ...
Clostridium perfringens
Microbiology
162
145-155
2016
-
-
2
-
-
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5
-
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1
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2
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1
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2
-
7
-
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2
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2
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2
2
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5
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1
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1
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2
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2
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3
3
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744335
Sah
Impact of mutating the key re ...
Escherichia coli, Escherichia coli K12
Biochemistry
54
3504-3513
2015
-
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1
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7
-
-
8
-
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3
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1
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2
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8
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1
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7
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8
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1
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2
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-
-
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8
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-
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8
8
742856
Shin
Mitochondrial MTHFD2L is a du ...
Mus musculus, Rattus norvegicus, Mus musculus C57BL/6
J. Biol. Chem.
289
15507-15517
2014
-
-
2
-
-
-
2
8
2
6
-
9
-
5
-
-
1
-
-
11
-
1
14
1
10
2
-
-
6
2
-
-
10
-
-
-
-
-
2
10
-
-
-
-
2
-
8
2
6
-
9
-
-
-
1
-
11
-
1
14
1
2
-
-
6
2
-
-
-
-
6
6
-
6
6
720406
Eadsforth
The crystal structure of Leish ...
Leishmania major, Leishmania major Fridlin
Mol. Biochem. Parasitol.
181
178-185
2012
-
-
1
1
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1
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2
2
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2
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1
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-
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2
1
2
-
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1
1
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1
1
1
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1
1
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2
2
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1
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2
1
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718743
Lee
Crystal structure of bifunctio ...
Thermoplasma acidophilum
Biochem. Biophys. Res. Commun.
406
459-463
2011
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1
1
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-
-
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1
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1
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1
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2
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14
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1
2
2
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1
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7
2
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2
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2
1
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Mitochondrial methylenetetrahy ...
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7
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654937
Casaite
-
Elucidation of enzymatic funct ...
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Purification and characterizat ...
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2
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2
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2
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1
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392333
Pawelek
Methenyltetrahydrofolate cyclo ...
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Biochemistry
37
1109-1115
1998
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7
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Pawelek
Methylenetetrahydrofolate dehy ...
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Kirk
-
A 5,10-methylenetetrahydrofola ...
Pisum sativum
Phytochemistry
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Pelletier J.N.; MacKenzie
Binding and interconversion of ...
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Biochemistry
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Enzymes for synthesis of 10-fo ...
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C1-Tetrahydrofolate synthase f ...
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Studies on the polyglutamate s ...
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Methylenetetrahydrofolate dehy ...
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Methylenetetrahydrofolate dehy ...
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A complex of N5,N10-methylenet ...
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Formyl-methenyl-methylenetetra ...
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392328
Yoshida
Comparative study on major pat ...
Bos taurus, Elaphe quadrivirgata, Gallus gallus bankiva, Ovis aries
J. Biochem.
72
1503-1516
1972
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392326
Cossins
-
Plant N5,N10-methylenetetrahyd ...
Pisum sativum
Phytochemistry
9
1463-1471
1970
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392306
Albrecht
Methylenetetrahydrofolate dehy ...
Enterococcus faecium
J. Bacteriol.
95
1779-1789
1968
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392310
Uyeda
Enzymes of clostridial purine ...
Clostridium cylindrosporum
J. Biol. Chem.
242
4378-4385
1967
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392312
Dalal
Purification of 5,10-methylene ...
Salmonella enterica subsp. enterica serovar Typhimurium, Salmonella enterica subsp. enterica serovar Typhimurium LT2
J. Biol. Chem.
242
3636-3640
1967
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392316
Yeh
Purification and properties of ...
Bos taurus
Biochim. Biophys. Acta
105
279-291
1965
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392313
Ramasastri
5,10-Methylenetetrahydrofolic ...
Saccharomyces cerevisiae
J. Biol. Chem.
237
1982-1988
1962
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